The present invention relates to substituted tetrahydropyrrolopyrazine compounds, processes for their preparation, pharmaceutical compositions containing these compounds and the use of these compounds for the preparation of pharmaceutical compositions for the treatment of pain and other conditions.
Treatment of pain, in particular of neuropathic pain, is of great importance in medicine. There is a worldwide need for pain therapies which are effective. The urgent need for action for targeted treatment of chronic and non-chronic states of pain appropriate for the patient, by which is to be understood successful and satisfactory pain treatment for the patient, is also documented in the large number of scientific works which have been published recently in the field of applied analgesics and of basic research into nociception.
Monoamine reuptake inhibitors from the class of tricyclic antidepressants (TCAs) have been successfully employed for treatment of depression since the 1960s. The relevance of dysfunctions of monoaminergic systems with psychiatric diseases is widely acknowledged on the basis of the preclinically and clinically demonstrated antidepressive actions of TCAs, selective serotonin reuptake inhibitors (so-called SSRIs), selective noradrenaline reuptake inhibitors, mixed serotonin and noradrenaline reuptake inhibitors (so-called SNRIs), monoamine oxidase inhibitors and modulators of various serotonin and noradrenaline receptor subtypes (Berman et al., Biol Psychiatry, 2002 Mar. 15; 51(6):469-73). Antidepressants moreover are important adjuvants in pain therapy, in particular for chronic pain. However, an independent analgesic action is induced by monoamine reuptake inhibitors, in that they activate the descending inhibition of spinal nociceptive signals. Good successes are also described in the treatment of urinary incontinence by use of monoamine reuptake inhibitors (Sorbera et al., Drugs of the future, 2000, vol. 25, page 907-916). Monoamine reuptake inhibitors are furthermore suitable for treatment of anxiety states, fibromyalgia, eating disorders, bulimia, hyperactivity (attention deficit hyperactivity disorder; ADHD), drug dependency, addiction and withdrawal, trichotillomania, skin diseases, such as postherpetic neuralgia and pruritus, memory disorders, cognitive disorders and Alzheimer's disease.
Therapeutic use of the antidepressants approved to date is limited by the undesirable side effects which often occur. There may be mentioned here in particular constipation, retention of urine, dryness of the mouth, accommodation disorders, orthostatic hypotension with tachycardia, sedation, serotonin syndrome, sexual dysfunctions, dizziness, cognitive dysfunctions and QT prolongations, incl. torsade de pointes. Disadvantages in the treatment of psychiatric diseases are a late onset of action, a high rate of recurrence and an absence of action in 20-30% of patients.